Case report of two siblings with type 2A von Willebrand disease involving a novel mutation within the calcium-binding site of the A2 domain of von Willebrand factor

Henry P. Igid, Kyaw Z. Thein, Michael Castine, Donald P. Quick

Research output: Contribution to journalArticlepeer-review

Abstract

Calcium-binding at the A2 domain protects von Willebrand factor (VWF) from cleavage by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS13) and is coordinated by five important residues (p.Asp1596, p.Arg1597, p.Ala1600, p.Asn1602, and p.Asp1498). Only variants of p.Arg1597 resulting in type 2A von Willebrand disease have been reported. We report a novel VWF variant, a heterozygous single nucleotide change, c.4493A>G, occurring at the p.Asp1498 residue of the calcium-binding site of the A2 domain in two sisters with type 2A von Willebrand disease. Modest increase in the VWF propeptide/VWF:Ag ratio (2.4 and 2.7) supports increased clearance of VWF. A literature review provided insight into the integral role of p.Asp1498 residue in calcium-binding and its role in the stabilization of other residues including p.Arg1597 and p.Asn1602. Studies done by other groups on engineered mutations involving p.Asp1498 reported increased susceptibility to ADAMTS13 proteolysis. Cellular studies are needed to confirm these mechanisms.

Original languageEnglish (US)
Pages (from-to)161-167
Number of pages7
JournalBlood Coagulation and Fibrinolysis
Volume30
Issue number4
DOIs
StatePublished - Jun 1 2019
Externally publishedYes

Keywords

  • calcium-binding site
  • mutation
  • p.Asp1498Gly
  • type 2A von Willebrand disease
  • von Willebrand disease

ASJC Scopus subject areas

  • Hematology

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